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Researchers at Case Western Reserve University's School of Medicine have found that a genetic process common to many species of rodents might be significant to the pace of human evolution.

Scientists historically have argued that evolution proceeds through gradual development of traits. But how can incremental changes apply to the binary switch between two sexes, male or female?

"What we addressed is a long-standing puzzle in natural history: why different types of rodents can exhibit profound differences in how male sex is determined in the embryo. Some rodent populations have both XY males and XY females, and in other populations the Y chromosome has disappeared entirely."

Michael Weiss, MD, PhD, chairman of the Department of Biochemistry, the Cowan-Blum Professor of Cancer Research, professor of biochemistry and medicine.

In a study published in Proceedings of the National Academy of Sciences, Weiss and his research team analyzed the Sry gene, which is part of the Y chromosome. This mammalian gene, which steers differentiation in the embryonic gonad toward the development of testes, begins the process leading to the birth of males.

In most mammals, including primates, the Sry gene is a conserved feature of the Y chromosome, ultimately giving rise to male anatomy.

Females generally have XX chromosomes and no Y.

But certain families of rodents common in South America, activation of the Sry gene seems to have uncertain consequences. Some of these animals have both XY males and XY females as normal parts of the population. Other related species have even lost the Y chromosome altogether.

Without the emergence of compensating ways of specifying sex, the species could not produce males—and would become extinct. For such rodents, therefore, evolution meant inventing entirely different methods of sex determination. These mammals have in essence evolved other ways to play nature's mating game.

The CWRU team attributed the rapid evolvability of sex determination in rodents to a novel protein domain added to the SRY protein. Scientists knew that this domain existed, but Weiss and his team wanted to understand more about its function in gene regulation and its role in evolution. The team determined that the new protein domain acts as a "genetic capacitor," providing a protective buffer to the Sry gene. This buffer allowed male development even when a mutation occurs elsewhere in the gene that might otherwise cause sex reversal—but the buffer is unstable over generations.

Slippage of DNA during the production of sperm can lead to sudden changes in the length of the buffer and the degree of protection. By analogy to a capacitor in an electric circuit, the team suggested that this domain can "discharge" to accelerate the pace of evolutionary change. The idea of a genetic capacitor was pioneered by MIT Professor Susan Lindquist in studies of heat-shock proteins in fruit flies in (Nature, "Hsp90 as a capacitor for morphological evolution") and the present paper extended this idea to the pace of mammalian evolution.

How did the Sry buffer arise? "We discovered that a genetic accident 20 million years ago in an ancestral rodent holds the key to solving this puzzle. A simple DNA repeat sequence (called a 'micro-satellite') invaded the Y chromosome and was incorporated into the Sry gene. This invasion accelerated the evolvability of Sry and probably the Y chromosome in general, enabling this subgroup of rodents to explore new molecular mechanisms of sex determination," Weiss said.

Weiss and his team will continue this research, but believe these initial results may have additional implications for our understanding of human evolution and genetics. Because rodents have higher mutation rates and shorter life spans, they also evolve more rapidly and so provide a natural laboratory for studies of mammalian evolution.

Research last year at MIT has shown that in humans and other primates the Y chromosome has been stable for at least 25 million years (Nature, Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes), which Weiss believes may reflect the absence of micro-satellite-related slippage in the Sry gene. Yet transcription strengths of the murine and human Sry factors are similar.

The research suggests that human SRY and its specification of male development has evolved to be just above a genetic threshold of activity, which may in turn enable human communities to benefit from a diversity of male characteristics and behaviors.

"A key lesson of this 20 million-year history is that maleness is a 'close call' as the Sry protein functions near the edge of ambiguity," Weiss explained. "We think that the 'genetic decision' in an embryo to create a testis (instead of an ovary) is tenuous in all social mammals, including us. The critical next question is why?"

The SRY high-mobility-group box recognizes DNA by partial intercalation in the minor groove: a topological mechanism of sequence specificity

Abstract
SRY, a putative transcription factor encoded by the sex-determining region of the human Y chromosome, regulates a genetic switch in male development. Impairment of this switch leads to intersex abnormalities of the newborn and is observed in association with mutations in the SRY DNA-binding domain [the high-mobility-group (HMG) box]. Here we show that the SRY HMG box exhibits a novel mechanism of DNA recognition: partial intercalation of a nonpolar side chain in the DNA minor groove. Base stacking (but not base pairing) is interrupted at the site of insertion. Sequence specificity reflects topological requirements of partial intercalation rather than direct readout of base-specific functional groups. Our results predict that the SRY HMG box inserts an alpha-helix into a widened minor groove at the center of a sharp DNA bend. A similar mechanism may underlie binding of SRY and homologous HMG proteins to four-way junctions (Holliday intermediates) and other noncanonical DNA structures.

About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu